This project is designed to determine the hypothalamic and pituitary contributions to aging of the reproductive endocrine system and to differentiate the specific effects of aging from those due to sex steroid depirvation. The loss of gonadal hormone secretion during the menopause makes it possible to isolate the independent effects of aging and changes in gonadal hormone secretion on the hypothalamic and pituitary components of the reproductive system. Younger (age 45-55) and older (age 70-80) postmenopausal women (PMW) will be studied before and after gonadal hormone replacement in one of three protocols designed to assess GnRH pulse frequency, quanity of GnRH (low dose GnRH antagonist) and differential control of gonadotropin secretion by GnRH (high dose GnRH antagonist). Protocol 289B will assess changes in hypothalamic GnRH secretion which occur with aging and hormonal replacement by determination of the overall quantity of GnRH secretion estimated using submaximal GnRH receptor blockade. Fifteen 3-month studies have now been completed (9 older and 6 younger PMW). Results to date indicate that suppression of LH in response to 5 mcg/kg of the NAL-GLU GnRH antagonist is not significantly different between baseline and estrogen treatment (55+/-2.1 and 59.4+/-2.3%, respectively), but is significantly greater with estrogen + progesterone treatment (68.2+/-3.7%; p<0.003), indicating no effect of estrogen alone on the quanity of GnRH secreted, but a significant decrease with the addition of progesterone. In this preliminary data, there is no evidence of a change in overall GnRH secretion with age. Protocol 289C will explore changes in the differential control of LH, FSH and free a-subunit (FAS) with age and hormonal replacement by complete blockade of the GnRH recptor using maximally suppressive doses of the NAL-GLU GnRH antagonist (150 mcg/kg). These studies also permit us to determine the effect of age and hormonal replacement on the disappearance of LH following blockade of the GnRH receptor, the effect of age and hormonal replacement on the isoform composition of LH, and the role of GnRH, gonadal hormones and age in the control of serum follistatin (FS) levels. Five 3-month studies have been completed in PMW (3 older and 2 younger). Preliminary analysis indicates that the degree to which FAS is controlled by GnRH is greater in PMW than in normally cycling women while there is no difference in the degree to which GnRH controls LH or FSH between these two groups. A very exciting finding is that total FS in serum is increased in response to GnRH receptor blockagde at baseline (consistent with the decrease in FS in GnRH deficient men treated with GnRH), but this effect is abolished in the presence of estrogen and estrogen + progesterone.